Therapies targeted to deplete B cells have been shown to be useful in treating a wide variety of B cell mediated diseases. For example, rituximab, the RITUXAN® antibody, which is a genetically engineered chimeric murine/human monoclonal antibody directed against human CD20 antigen (commercially available from Genentech, Inc., South San Francisco, Calif., U.S.) is used for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B cell non-Hodgkin's lymphoma. Results from rituximab clinical trials and case studies (Biogen Idec, Cambridge, Mass., USA and Genentech, South San Francisco, Calif., USA) report therapeutic benefits not only in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), but also in patients with less common autoimmune diseases such as refractory dermatomyositis, type II mixed cryoglobulinemia, Wegener's granulomatosis, autoimmune hemalytic anemia, idiopathic thrombocytopenia, and immunoglobulin M (IgM) polyneuropathies (Gorman C, et al., (2003) Arthritis Res Ther 5:S17-S21; Somer B G, et al., (2003) Arthritis Rheum 49:394-398).
Currently, the activity of B cell depleting therapies in subjects is sometimes monitored by measuring actual B cell levels in the blood during B cell depletion and repletion (recovery). Alternatively or additionally, the activity of B cell depleting therapies have been evaluated by monitoring markers in blood traditionally associated with the disease. For example, for certain autoimmune diseases, autoantibodies such as double-stranded DNA antibodies have been monitored. None of these methods give a clear, contemporaneous view of the B cell population in other areas of the subject. Obtaining biopsies of tissues (e.g., spleen, lymph nodes and joints) of patients or evaluating other bodily fluid (e.g., spinal fluid, synovial fluid) is often not an option, or at the very least, inconvenient.
One polypeptide that is elevated in several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome, is the BAFF polypeptide (Cheema, G. S, et al., (2001) Arthritis Rheum. 44:1313-1319; Groom, J., et al, (2002) J. Clin. Invest. 109:59-68; Zhang, J., et al., (2001) J. Immunol. 166:6-10). BAFF (also known as BLyS, TALL-1, THANK, TNFSF13B, or zTNF4) is a member of the TNF ligand superfamily that is essential for B cell survival and maturation (reviewed in Mackay & Browning (2002) Nature Rev. Immunol. 2:465-475). BAFF can be found in secreted from or on the cell-surface of monocytes, macrophages, dendritic cells, and neutrophils, but not B cells (Nardelli B, et al. (2000) Blood 97: 198-204; Scapini P, et al. (2003) J Exp Med 197:297-302). BAFF overexpression in transgenic mice leads to B cell hyperplasia and development of severe autoimmune disease (Mackay, et al. (1999) J. Exp. Med. 190:1697-1710; Gross, et al. (2000) Nature 404:995-999; Khare, et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97:3370-33752-4).
Furthermore, BAFF levels correlate with disease severity, suggesting that BAFF may play a direct role in the pathogenesis of these illnesses. BAFF binds to three members of the TNF receptor superfamily, TACI, BCMA, and BR3 (also known as BAFF-R) (Gross, et al., supra; Thompson, J. S., et al., (2001) Science 293, 2108-2111; Yan, M., et al. (2001) Curr. Biol. 11:1547-1552; Yan, M., et al., (2000) Nat. Immunol. 1:37-41; Schiemann, B., et al., (2001) Science 293:2111-2114). Of the three, only BR3 is specific for BAFF; the other two receptors also bind the related TNF family member, APRIL. Comparison of the phenotypes of BAFF and receptor knockout or mutant mice indicates that signaling through BR3 mediates the B cell survival functions of BAFF (Thompson, et al., supra; Yan, (2002), supra; Schiemann, supra). In contrast, TACI appears to act as an inhibitory receptor (Yan, M., (2001) Nat. Immunol. 2, 638-643), while the role of BCMA is less clear (Schiemann, supra).
Currently, a blocking mAb targeting BAFF (Lymphostat-B™, Human Genome Sciences, Rockville, Md.) is in clinical trials in RA and SLE patients, TACI-Fc (ZymoGenetics, Seattle, Wash. and Serono, Geneva, CH) is in clinical trials in SLE patients and BAFF-R:Fc (also called BR3-Fc) (Biogen Idec, Cambridge, Mass. and Genentech, South San Francisco, Calif.) is in clinical development. Reports of the data from the phase II trial with Lymphostat-B™ in rheumatoid arthritis stated that patients experienced a reduction in select B cell populations (McKay, J., et al., 69th Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals. Oral Presentation #1920 (Nov. 16, 2005)).
The rationale for using inhibitors of BAFF to treat B cell mediated diseases is clear. However, understanding the scope of the use of BAFF as a marker, not as a target for a therapeutic agent, and understanding when and how to use it as a marker in treatment regimens is less clear. The answer to these questions and others are described below.